Immune recovery in tumor microenvironment ofTP53-mutated AML following venetoclax combination therapy

Highlights

• Single-cell RNA sequencing of bone marrow from TP53-mutated AML patients showed a decrease in cells expressing anti-apoptotic genes like BCL2 and MCL1 after venetoclax and azacitidine treatment.

• Immune cells increased both in number and in gene expression levels associated with cytotoxicity post venetoclax combination therapy, verifying immune recovery.

• Residual AML cells expressed CD47 and CLL1, suggesting a role for ancillary treatment targeting antigens expressed on residualTP53-mutated AML cells.

The BCL-2 inhibitor venetoclax combined with the hypomethylating agent azacitidine or with low-dose cytarabine significantly improves response rates and overall survival (OS) for newly diagnosed unfit and relapsed / refractory (R/R) acute myeloid leukemia (AML) patients. We retrospectively analyzed our experience with venetoclax combination therapy in 41 unfit AML patients (23 untreated, 18 R/R). Overall response rates were 78.3% for untreated patients and 61.1% for R/R patients.TP53alterations were observed in 13 patients (31.7%) and were identified as an independent predictor of poor outcome (p=0.0008). We further conducted single-cell RNA sequencing in bone marrow, sampled before and after venetoclax and azacitidine treatment, of threeTP53-mutated AML patients who achieved complete remission (CR) or CR with incomplete hematologic recovery. After treatment, numbers of cells expressing anti-apoptotic genes such asBCL2andMCL1decreased. CD4 T cells, cytotoxic CD8 T cells, and NK cells significantly increased both in number and in levels of gene expression associated with cytotoxicity post-treatment, confirming immune recovery in the tumor microenvironment. Residual AML cells expressedCD47andCLEC12A(CLL1). These results indicate that venetoclax combination therapy of AML is promising in real-world clinical practice and suggest a role for ancillary treatment targeting antigens expressed on residual AML cells as a therapeutic strategy inTP53-mutated AML.